Mediterranean G6PD variant mitigates expression of DNA methyltransferases and right heart pressure in experimental model of pulmonary hypertension.

Autor:	Jacob C; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., Kitagawa A; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., Signoretti C; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., Dzieciatkowska M; Department of Biochemistry & Molecular Genetics, School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, USA., D'Alessandro A; Department of Biochemistry & Molecular Genetics, School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, USA., Gupte A; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., Hossain S; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., D'Addario CA; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., Gupte R; Department of Pharmacology, New York Medical College, Valhalla, New York, USA., Gupte SA; Department of Pharmacology, New York Medical College, Valhalla, New York, USA. Electronic address: s_gupte@nymc.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Dec; Vol. 298 (12), pp. 102691. Date of Electronic Publication: 2022 Nov 11.
DOI:	10.1016/j.jbc.2022.102691
Abstrakt:	DNA methylation potentially contributes to the pathogenesis of pulmonary hypertension (PH). However, the role of DNA methyltransferases (DNMTs: 1, 3a, and 3b), the epigenetic writers, in modulating DNA methylation observed in PH remains elusive. Our objective was to determine DNMT activity and expression in the lungs of experimental rat models of PH. Because the activity of DNMTs is metabolically driven, another objective was to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in regulating DNMT expression and activity in the lungs of novel loss-of-function Mediterranean G6PD variant (G6PD S188F ) rats. As outlined for modeling PH, rats injected with sugen5416 (SU) were placed in a hypoxia (Hx) chamber set at 10% oxygen for 3 weeks and then returned to normoxia (Nx) for 5 weeks (SU/Hx/Nx). Rats kept in atmospheric oxygen and treated with SU were used as controls. We assessed the activity and expression of DNMTs in the lungs of rats exposed to SU/Hx/Nx. WT rats exposed to SU/Hx/Nx developed hypertension and exhibited increased DNMT activity and Dnmt1 and Dnmt3b expression. In G6PD S188F rats, which developed less of a SU/Hx/Nx-induced increase in right ventricle pressure and hypertrophy than WT rats, we observed a diminished increase in expression and activity of DNMTs, DNA hypomethylation, increased histone acetylation and methylation, and increased expression of genes encoding NOS3 and SOD2-vascular-protective proteins. Collectively, increased DNMTs contribute to reduced expression of protective genes and to the pathogenesis of SU/Hx/Nx-induced experimental PH. Notably, G6PD regulates the expression of DNMTs and protective proteins in the lungs of hypertensive rats. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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